Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis

Background: Myelofibrosis (MF) patients (pts) who are relapsed or refractory (R/R) to JAK inhibitor (JAKi) treatment have a poor prognosis with a median overall survival of 11-13 months (Mascarenhas 2020; Palandri 2020). MF is characterized by excessive production of mouse double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, in CD34⁺ progenitor cells. Navtemadlin is a potent, selective, orally available MDM2 inhibitor that restores p53 function. Preclinically, navtemadlin drives apoptosis of TP53 wild-type (TP53^WT) CD34⁺ MF cells through modulation of B cell lymphoma (BCL-2) family proteins. In a phase 2 study, navtemadlin showed clinically meaningful activity with disease-modifying potential in MF pts who were R/R to JAKi (Al-Ali 2020; Verstovsek 2022; Vachhani 2023).

Aim: To evaluate the efficacy and safety of navtemadlin monotherapy vs best available therapy (BAT) in the phase 3 BOREAS study (NCT03662126).

Methods: The BOREAS study enrolled TP53^WT adults with primary or secondary MF who were R/R to JAKi treatment (JAKi-intolerant or JAKi-ineligible pts were excluded); ECOG 0-2, intermediate- (int-) or high-risk MF per DIPSS, platelets ≥50x10⁹/L, and peripheral blasts <10%. Pts were randomized 2:1 to receive navtemadlin monotherapy 240 mg once-daily (Day 1-7/28-day cycle) or BAT (monotherapy or combinations: hydroxyurea, chemotherapy, IMiDs, and supportive care; JAKi were excluded). Pts were required to have a 28-day JAKi “wash-out” period prior to baseline MRI/CT. Crossover to navtemadlin was allowed at Week 24 or at time of disease progression. Anti-diarrhea prophylaxis was administered for the first two cycles and anti-nausea prophylaxis was given with every cycle for the seven days of navtemadlin treatment. The primary endpoint was rate of spleen volume reduction ≥35% (SVR35) at Week 24 by MRI/CT (blinded central review). The key secondary endpoint was the rate of total symptom score reduction ≥50% (TSS50) at Week 24 by MFSAF v4.0.

Results: As of March 11, 2024 (enrollment stopped in August 2023), 183 pts were randomized (123 pts on navtemadlin and 60 pts on BAT; intention-to-treat population [ITT]) in 23 countries at 181 sites. Baseline characteristics were well balanced between the arms and included: int-1/int-2/high-risk MF per DIPSS (34%/50%/15%), median spleen volume of 2310 cm³, median TSS of 20.8, prior therapy range of 1-6 (99% had ruxolitinib [rux]), median time from initial MF diagnosis was 47.6 months, 34% of pts had platelets <100x10⁹/L, 48% had a bone marrow fibrosis of grade 3, 70% had the JAK2^V617F driver mutation, and 77% had ≥1 high molecular risk mutation (≥2 in 23%).

At Week 24 (ITT), 15% (18/123) of pts vs 5% (3/60) achieved SVR35 (p=0.08) and 24% (30/123) vs 12% (7/60) achieved TSS50 (p=0.05) with navtemadlin vs BAT, respectively. Forty percent (24/60) of pts on BAT crossed over to navtemadlin. Marked reductions in disease biomarkers (ie, bone marrow fibrosis, driver mutation allele burden, and blood CD34⁺ progenitors) were greater with navtemadlin, suggesting potential disease modification. At the time of data cut, transformation to AML occurred in 1.6% (2/123) of pts on navtemadlin vs 3.3% (2/60) on BAT; all four pts were TP53^WT.

At a median follow-up of 10.7 months, the most common hematologic (heme) grade 3/4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (37% vs 21%), anemia (29% vs 25%), and neutropenia (24% vs 12%) with navtemadlin vs BAT, respectively. Gastrointestinal (GI) grade 3/4 TEAEs were diarrhea (5% vs 2%), nausea (3% vs 0%), and vomiting (2% vs 0%) with navtemadlin vs BAT, respectively. Mean platelet and hemoglobin levels remained stable over the course of study treatment. Dose reductions and discontinuations for heme TEAEs were 26% and 3%, and for GI TEAEs were 8% and 0%.

Conclusion: BOREAS is the first randomized, global phase 3 study conducted solely in MF pts R/R to JAKi to report results. In this phase 3 study, navtemadlin monotherapy was safe and effective, demonstrating clinically relevant efficacy with disease-modifying potential. The rate of SVR35 and TSS50 at Week 24 was three-fold and two-fold higher with navtemadlin vs BAT, validating the novel approach of MDM2 inhibition in pts with MF. Further studies of navtemadlin in MF are warranted, including as add-on therapy to rux treatment in JAKi-naive pts who have a suboptimal response to rux (POIESIS; NCT06479135).

Mascarenhas:CTI BioPharma/SOBI: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel Support, Speakers Bureau; MorphoSys: Consultancy; Merck: Consultancy; PharmaEssentia: Consultancy, Research Funding; Disc: Consultancy; GSK: Consultancy; Blueprint Medicines: Consultancy; Ariad: Speakers Bureau; Novartis: Consultancy, Other: Travel Support , Research Funding, Speakers Bureau; Sumitomo: Consultancy; Karyopharm: Consultancy; Pfizer: Research Funding; Keros: Consultancy; Bristol Myers Squibb: Research Funding; Icahn School of Medicine at Mount Sinai: Current Employment; Ajax: Research Funding; Roche: Consultancy; Geron: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Speakers Bureau; Astellas: Research Funding. Popov:Colentina Clinical Hospital: Current Employment. Mohan:Taiho: Research Funding; Kartos Therapeutics: Research Funding; Karyopharma: Research Funding; Ichnos: Research Funding; Incyte: Research Funding. Özkurt:Gazi University: Current Employment. Kiladjian:Novartis: Consultancy; GSK: Consultancy; Abbvie: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; AOP Orphan: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria. Al-Ali:Stemline: Honoraria; Blueprint: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Blueprint: Honoraria; AOP: Consultancy, Honoraria; Alexion: Other: Travel grant; MSD: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel grant; BMS: Consultancy, Research Funding; GSK: Consultancy, Honoraria; Incyte: Research Funding; Novartis: Consultancy, Honoraria. Perkins:GSK: Consultancy, Honoraria; Abbvie: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Qamoos:Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company. McGreivy:Kartos Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Rothbaum:Iovance Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company; Telios Pharma: Consultancy, Patents & Royalties; Quogue IP Holdings: Patents & Royalties; Quogue Capital: Current Employment; Kartos Therapeutics: Consultancy, Patents & Royalties; Telios Pharma: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Verstovsek:Kartos Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.